Despite successes with high-dose therapy, long-term disease free survival is uncommon in myeloma. This findings have prompted a search for novel therapeutic interventions directed against targets that are unique to myeloma. We have preliminary results from multiple clinical trials that confirm immune competence of myeloma patients, induction of antigen-specific (Idiotype) immune responses and feasibility and effectiveness of dendritic cell vaccines. Using DC-myeloma cell fusions of both human cells and in a murine model, we have data confirming presentation of a wide array of myeloma-related antigens and the development of CTLs able to lyse primary myeloma cells. Based on these results we propose to evaluate DC-MM fusion cell vaccination and subsequently compare it with idiotype-pulsed DC vaccination to evaluate the hypothesis that fusion cells with both MHC class I and II presentation of multiple antigens will be more potent in generating tumor specific immunity than the strategy of loading of single antigen onto DC. Based on the hypothesis that antigen-specific vaccination targeting a single antigen will lead to an 'escape phenomenon' with outgrowth of cells not expressing that antigen, we are beginning to identify series of immunogens with antibody responses in myeloma patients. We propose to perform Serological Analysis of Recombinant cDNA Expression Library (SEREX) pre and post vaccination and analyze genes with responses only post-vaccination to identify antigens recognized following vaccination. With a view to evaluate the hypothesis that in vivo immune responses generated by tumor cell vaccination will lead to identification of tumor specific-immunogens that can be exploited for antigen-specific immunotherapy, the following aims will be pursued: Specific Aim 1: To evaluate toxicity, achievable dose and efficacy of the MM/mature DC fusion cell vaccine strategy; Specific Aim 2: To compare efficacy and toxicity of MM/mature DC fusion cell (FC) vaccine strategy with the Id-pulsed DC vaccine; Specific Aim 3 (a) To identify and evaluate novel immune targets identified in vivo during the ongoing vaccine studies (SEREX and gene array data); (b) Evaluate immune responses against these antigens in myeloma patient samples and normal donor samples; Specific Aim 4: To evaluate antigen-specific vaccines in generating tumor specific immune responses in patients with multiple myeloma.